8jv7 | pdb_00008jv7

Cryo-EM structure of the panda P2X7 receptor in complex with PPADS

spinqualitylabelsall models 8jv7, resolution 3.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8jv7 is a 3 chain structure with sequence from Ailuropoda melanoleuca. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.6Å Ligands: NAG, UO6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function G1M6C4_AILME Receptor for ATP that acts as a ligand-gated ion channel.[RuleBase:RU000681] Publication Abstract from PubMed P2X receptors are extracellular ATP-gated ion channels that form homo- or heterotrimers and consist of seven subtypes. They are expressed in various tissues, including neuronal and nonneuronal cells, and play critical roles in physiological processes such as neurotransmission, inflammation, pain, and cancer. As a result, P2X receptors have attracted considerable interest as drug targets, and various competitive inhibitors have been developed. However, although several P2X receptor structures from different subtypes have been reported, the limited structural information of P2X receptors in complex with competitive antagonists hampers the understanding of orthosteric inhibition, hindering the further design and optimization of those antagonists for drug discovery. We determined the cryogenic electron microscopy (cryo-EM) structures of the mammalian P2X7 receptor in complex with two classical competitive antagonists of pyridoxal-5'-phosphate derivatives, pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) and pyridoxal phosphate-6-azophenyl-2',5'-disulfonic acid (PPADS), and performed structure-based mutational analysis by patch-clamp recording as well as molecular dynamics (MD) simulations. Our structures revealed the orthosteric site for PPADS/PPNDS, and structural comparison with the previously reported apo- and ATP-bound structures showed how PPADS/PPNDS binding inhibits the conformational changes associated with channel activation. In addition, structure-based mutational analysis identified key residues involved in the PPNDS sensitivity of P2X1 and P2X3, which are known to have higher affinity for PPADS/PPNDS than other P2X subtypes. Structural insights into the orthosteric inhibition of P2X receptors by non-ATP analog antagonists.,Sheng D, Yue CX, Jin F, Wang Y, Ichikawa M, Yu Y, Guo CR, Hattori M Elife. 2024 Apr 5;12:RP92829. doi: 10.7554/eLife.92829. PMID:38578670 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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